Project Summary: The prostate-specific antigen (PSA) has been widely used as a biomarker in current clinical practice to screen men for prostate cancer, although issues associated with this method including high false-positive rate are well known. This is because in addition to prostate cancer, infection and chronic inflammation or benign prostatic hyperplasia (BPH) may also cause elevations in PSA levels. Therefore, there is tremendous interest in developing other approaches with higher specificity for improved detection of prostate cancer in recent years. Despite the significant progress in developing a number of new molecular biomarkers, none of them has been successful enough to replace PSA test so far. On the other hand, using exfoliated prostate cancer cells isolated from urine specimens for diagnosing the carcinoma of the prostate has long been proposed. Although the examination at cellular levels provides excellent specificities in contrast to PSA tests, past attempts at diagnosing prostate cancer via traditional urine cytology were abandoned due to unacceptably low sensitivities. The challenge in increasing sensitivity mainly stems from lacking sensitive and specific markers that allow visualization and differentiation of malignant prostate cancer cells through immunofluorescence labeling. Instead of using immunofluorescence labeling, a new approach has been proposed in this project to use cell refractive indices (RI) as a native contrast parameter for label-free, noninvasive detection of prostate cancer, because RI properties directly reflect certain macromolecular constituents and their nanostructures of a cell, which are different between cancer and normal cells. A novel imaging system based on a patented photonic crystal biosensor will be designed and constructed for label-free detection of malignant prostate cancer cells from urine with unparalleled sensitivity and specificity. Successful development of the proposed technology will allow reducing unnecessary multicore prostate biopsy due to false- positive PSA results and address the unmet urgent demand of a noninvasive, accurate approach for prostate cancer screening. Furthermore, the proposed technology is highly transformative, which may potentially lead to other widespread applications, such as detection of other cancer or diseases and monitoring therapeutic treatment effects.